The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
Yersinia pestis (YP), a facultative anaerobe, is a Gram-negative bacillus. It is the etiological agent of plague, a zoonotic disease usually transmitted to humans from infected rodents via the bite of an infected flea. YP infection can result in three forms of the disease: (i) bubonic, (ii) septicemic and/or (iii) pneumonic plague. Pneumonic plague is highly contagious and easily transmitted among humans via airborne droplets, resulting in a rapid onset of disease and a mortality rate approaching 100% if treatment is delayed more than 24-hour postexposure.
Recently, plague has attracted a considerable attention because of its potential misuse as a biological warfare agent. The US Centers for Disease Control and Prevention regards Yersinia pestis as a type A bioterrorism threat. Most experts agree that a large plague outbreak would put health-care resources under severe pressure given the disease's inherent communicability, rapid clinical course, and high mortality if left untreated. Thus, it is imperative to develop an ideal plague vaccine for human use.
Historically, plague was a fatal infectious disease afflicting human populations, leading to millions of deaths. Yersinia pestis infections have led to three great pandemics that have caused the deaths of millions of individuals throughout history. The first was in the Mediterranean area in the 5th to 6th centuries AD, and the second was in Europe between the 8th and 14 centuries AD, both killing about one-half of the existing population. The third started in China in the 19th century and is still ongoing. The disease is transmitted to human beings from animals (cats and rats) by the infected fleas that they carry. Human to human transmission can occur through contact with the bodily fluids or aerosols produced by late stage infected individuals (1). Because millions of animals are infected worldwide in deserts, the steppes, mountains and forest (2), this disease will probably never be eradicated. Although there are antibiotics for treatment of these infections, the mortality is still high due to the rapid rate of the spread of the infection, once it is established in a human subject. There continue to be isolated, sporadic outbreaks of infections within the United States and around the world: (a) the 1994 plague outbreak from India; (b) the death of a woman in 1984 in the Lake Tahoe area who contracted the disease from her cat (3); (c) A case of bubonic plague in a 58 year old man was reported in 2011 in New Mexico; and (d) ground squirrels infected with the plague were recently reported in the San Diego area.
To date, there are no approved vaccines for Yersinia pestis. It is still very difficult to protect against pneumonic plague induced by inhalation of contaminated aerosols using vaccination. Accordingly, YP remains a bioterrorist threat for which there is no satisfactory countermeasure. YP is capable of spreading very rapidly in a human subject because of the Yersinia Outer Proteins (Yops) which block the immune response against YP, and kill the cells into which YP is taken up (4-5). One of these Yops is LcrV, a 41-kDa protein that is at the tip of the type III needle translocation complexes, and is required for the secretion of two other Yops: YopB and YopD (6-7). Another of these Yops is F1, the capsular pilus antigen that covers the outer wall of YP (8-9), and thereby prevents the uptake and killing of YP by macrophages (8). LcrV is involved in translocation of toxins from the YP bacterial cell to the cytoplasm of the YP infected host cell and F1 is a protein on the outer surface of YP that prevents phagocytosis of YP by macrophages (5). These two proteins are important to the virulence of YP since the administration of antibodies to these two proteins (singly or in combination) can protect mice from the effects of lethal doses of YP (10). Antibodies to these two proteins interact synergistically in protecting mice from YP challenge (10-11). While LcrV is required for virulence, F1 is dispensable (11-12).